Use of cyclohexenone derivatives in the manufacture of a medicament for treating diabetic complications

ABSTRACT

A preventive and/or therapeutic agent for diabetes complications, which comprises as an effective ingredient a cyclohexenone long-chain alcoholic derivative represented by the following formula (1): wherein, R 1 , R 2  and R 3  each independently represents a hydrogen atom or a methyl group and X represents a linear or branched C 10-28  alkylene or alkenylene group. The cyclohcxcnone long-chain alcoholic derivative of the present invention significantly suppresses a reduction in a peripheral nerve conduction rate and alleviates the hypofunction of the bladder so that it is useful as a preventive and/or therapeutic agent for diabetes complications, particularly, for diabetic neuropathy.

TECHNICAL FIELD

[0001] The present invention relates to a preventive and/or therapeuticagent for diabetic complications typified by diabetic neuropathy.

BACKGROUND ART

[0002] Diabetes is a complex disease caused by hyperglycemia. As itsessential treatment, the blood sugar level is controlled, in most casesby injection of insulin. What is really troublesome for those sufferingfrom diabetes is, however, the advance to diabetic complications. Asdiabetic complications, diabetic retinopathy, diabetic nephropathy,diabetic angiopathy and diabetic neuropathy are known. In order toprevent the onset of diabetic complications or to retard the advance ofthem, proper blood sugar control is necessary over a long period oftime. It is known that the longer the suffering period, the higher theincidence of diabetic complications.

[0003] As one of the factors for causing such diabetic complications,mentioned is abnormal acceleration of a polyol metabolic pathway (K. H.Gabbay, N. Eng. J. Med., 288, 831(1973)). The enzyme controlling thispolyol metabolic pathway is aldose reductase (AR). An AR inhibitor isnow used widely as a remedy for diabetic neuropathy. Diabeticcomplications occur not by one factor but by the tangle of variousfactors over a long period of time so that a medicament having mechanismof single action cannot be regarded as an absolute remedy.

[0004] An object of the present invention is therefore to provide anovel preventive and/or therapeutic agent for diabetic complications,particularly for diabetic neuropathy.

DISCLOSURE OF THE INVENTION

[0005] With the foregoing in view, the present inventors carried out anextensive investigation on low molecular compounds capable of protectingthe function of the peripheral nerve from being damaged by diabetes. Asa result, it has been found that long-chain alcohols having acyclohexenone skeleton represented by the below-described formula (1)have excellent peripheral-nerve-function protecting action, leading tocompletion of the present invention.

[0006] In addition, the present invention is to provide a pharmaceuticalcomposition for preventing and/or treating diabetic complications, whichcomprises the cyclohexenone long-chain alcoholic derivative and apharmaceutically acceptable carrier.

[0007] Also, the present invention is to provide use of thecyclohexenone long-chain alcoholic derivative for the manufacture of apreventive and/or therapeutic agent for diabetic complications.

[0008] Further, the present invention is to provide a method forpreventing and/or treating diabetic complications, which comprisesadministering the cyclohexenone long-chain alcoholic derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

[0009] In the present invention, there is thus provided a remedy fordiabetic complications, which comprises a cyclohexenone long-chainalcoholic derivative represented by the following formula (1):

[0010] [wherein, R¹, R² and R³ each independently represents a hydrogenatom or a methyl group and X represents a linear or branched C₁₀₋₂₈alkylene or alkenylene group].

[0011] In the cyclohexenone long-chain alcoholic derivatives representedby the formula (1), X represents a linear or branched C₁₀₋₂₈ alkyleneand alkenylene group. The branched alkylene or alkenylene groupcontains, as the side chain, a C₁₋₁₀ alkyl group. Examples of the alkylgroup as the side chain include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl and decyl groups.Among them, the methyl group is particularly preferred.

[0012] Substitution of the side chain to a linear alkylene or alkenylenegroup (which means an alkene structure having at least one carbon-carbondouble bond) is preferably at the 3- and/or 7-position. As X, linearC₁₀₋₂₈ alkylene groups are preferred, with linear C₁₀₋₁₈ alkylene groupsbeing particularly preferred.

[0013] R¹, R² and R³ each independently represents a hydrogen atom or amethyl group. More preferably, at least one of them represents a methylgroup.

[0014] The compound represented by the above-described formula (1) mayexist as a pharmaceutically acceptable salt, or a solvate or hydratethereof. The compound (1) has various isomers and these isomers are alsoembraced by the present invention.

[0015] The cyclohexenone long-chain alcoholic derivative represented bythe formula (1) can be prepared, for example, in accordance with thefollowing Process A or Process B.

[0016] [wherein, R^(1a), R^(2a) and R^(3a) each independently representsa hydrogen atom or a methyl group with the proviso that at least one ofthem represents a methyl group, Ph stands for a phenyl group and X, R¹,R² and R³ have the same meanings as described above].

[0017] Described specifically, the compound (1) is available by reactingcyclohexenone (2) or methyl-substituted-2-cyclohexen-1-one (3) with aphenylsulfinic acid salt in the presence of an acid, reacting theresulting compound (4) with ethylene glycol, reacting the resultingketal derivative (5) with a ω-halogenoalkanol or ω-halogenoalkenol, andsubjecting the resulting compound (6) to acid treatment to eliminate theprotective group.

[0018] The methyl-substituted-2-cyclohexen-1-one (3) used here as a rawmaterial is available by reacting methyl-substituted cyclohexanone witha trialkylsilyl halide in the presence of butyl lithium, followed byoxidation in the presence of a palladium catalyst.

[0019] The reaction of cyclohexenone (2) ormethyl-substituted-2-cyclohexen-1-one (3) with a phenylsulfinic acidsalt, for example, sodium phenylsulfinate is preferably effected in thepresence of an acid such as hydrochloric acid, sulfuric acid orphosphoric acid at 0 to 100° C. for 5 to 40 hours.

[0020] As the ω-halogenoalkanol to be reacted with the ketal derivative(5), a ω-bromoalkanol is preferred. The reaction between the ketalderivative (5) with the ω-halogenoalkanol is preferably effected in thepresence of a metal compound such as butyl lithium under low temperatureconditions.

[0021] The elimination of the phenylsulfonyl and ketal-protective groupsfrom the compound (6) so obtained is preferably effected by reacting itwith an acid such as paratoluenesulfonic acid.

[0022] [wherein, X¹ represents a C₉₋₂₇ alkylene or alkenylene group, Acstands for an acyl group and R¹, R², R³ and Ph have the same meanings asdescribed above].

[0023] Described specifically, the compound (1a) can be obtained byreacting the compound (7) [available in accordance with, for example,Tetrahedron, 52, 14891-14904(1996)] with ω-bromoalcohol (8), eliminatingthe phenylsulfonyl group from the resulting compound (9), protecting thehydroxy group of the resulting compound (10), oxidizing the resultingcompound (11), and then eliminating the hydroxy-protecting group fromthe resulting compound (12).

[0024] The reaction of the compound (7) with the ω-bromoalcohol (8) ispreferably conducted in the presence of a metal compound such as butyllithium under low temperature conditions.

[0025] The phenylsulfonyl group is eliminated from the compound (9), forexample, by reacting the compound with a phosphate salt in the presenceof sodium amalgam.

[0026] As the hydroxy-protecting group of the compound (10), an acetylgroup is preferred. The protection reaction is conducted, for example,by reacting the compound (10) with acetic anhydride.

[0027] The compound (11) is oxidized by reacting it with an alkylhydroperoxide such as t-butyl hydroperoxide in the presence of a metalcompound such as ruthenium trichloride.

[0028] The deprotection of the compound (12) is preferably conducted byhydrolyzing it in the presence of a base such as potassium carbonate.

[0029] The cyclohexenone long-chain alcoholic derivatives (1) thusobtained significantly suppress lowering in a stimulus conduction rateof the peripheral nerve in animal models of diabetes, therebysignificantly alleviating hypofunction of the urinary bladder such asdysuria as will be described later in test, so that they are useful as apreventive and/or therapeutic agent for diabetic complications,particularly diabetic neuropathy, in mammals including human.

[0030] The cyclohexenone long-chain alcoholic derivatives (1) of thepresent invention are low molecular compounds so that they can beadministered either orally or parenterally (intramuscularly,subcutaneously, intravenously or by way of suppository).

[0031] Oral preparations can be formulated into tablets, coveredtablets, coated tablets, granules, capsules, solutions, syrups, elixirs,or oil or aqueous suspensions in a manner known per se in the art afteraddition of an excipient and if necessary a binder, a disintegrator, alubricant, a colorant and/or a corrigent. Examples of the excipientinclude lactose, corn starch, saccharose, glucose, sorbitol andcrystalline cellulose. Examples of the binder include polyvinyl alcohol,polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic,tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylstarch and polyvinyl pyrrolidone.

[0032] Examples of the disintegrator include starch, agar, gelatinpowder, crystalline cellulose, calcium carbonate, sodium bicarbonate,calcium citrate, dextran and pectin; those of the lubricant includemagnesium stearate, talc, polyethylene glycol, silica and hardenedvegetable oil. As the colorant, pharmaceutically acceptable ones as anadditive can be used. Examples of the corrigent include cocoa powder,menthol, aromatic acid, peppermint oil, camphor and cinnamon powder. Thetablet can also be used in the form of a coated tablet available byapplying sugar coating, gelatin coating or the like to granules asneeded.

[0033] Injections, more specifically, subcutaneous, intramuscular orintravenous injections are formulated in a manner known per se in theart by adding a pH regulator, buffer, stabilizer and/or preservative asneeded. It is also possible to fill the injection solution in a vial orthe like and lyophilize it into a solid preparation which isreconstituted immediately before use. One dose is filled in a vial oralternatively, multiple doses are filled in one vial.

[0034] For a human adult, the dose of the invention compound as amedicament usually falls within a range of from 0.01 to 1000 mg/day,with a range of from 0.1 to 100 mg/day being preferred. This daily doseis administered once a day or in 2 to 4 portions a day.

EXAMPLES

[0035] The present invention will hereinafter be described morespecifically by Examples.

[0036] Preparation Example 1

[0037] (1) To a 20 ml THF solution of 7 ml of N,N-diisopropylamine, 35.4ml of a 1.4M n-butyl lithium solution was added dropwise at −78° C.,followed by stirring at 0° C. for 30 minutes. The resulting diisopropylaminolithium (LDA) solution was then added dropwise to a 10 ml THFsolution of 4 ml of 4-methylcyclohexan-1-one at −78° C.. After stirringat −78° C. for 1 hour, 6.5 ml of trimethylsilyl chloride was addeddropwise. After stirring at room temperature for 1 hour, the reactionmixture was poured into an aqueous sodium bicarbonate solution. Theresulting mixture was extracted with ether. The organic layer was washedwith saturated saline, dried over magnesium sulfate and distilled underreduced pressure to remove the solvent. Distillation under reducedpressure yielded 5.83 g of 4-methyl-1-(trimethylsilyloxy)-1-cyclohexene(yield: 96%).

[0038] 4-Methyl-1-(trimethylsilyloxy)-1-cyclohexene

[0039] Molecular weight: 184 (C₁₀H₂₀OSi)

[0040] TLC: (hexane:ethyl acetate=8:2) Rf=0.8

[0041]¹H-NMR (200 MHz, CDCl₃) δ: 0.17(s,9H,Si-(CH₃)₃),0.94(d,J=6.2Hz,3H,H-7), 1.2-1.43(m,1H,H-4), 1.57-1.76(m,3H,H-3,6),1.88-2.14(m,3H,H-5), 4.8-4.83(m,1H,H-2).

[0042]¹³C-NMR (50MHz, CDCl₃) δ: 0.3(Si—(CH₃)₃), 21.2(C-7), 28.3(C-4),29.6(C-5), 31.3(C-6), 32.3(C-3), 103.5(C-2), 150.1(C-1).

[0043] IR(NaCl): 3052, 3021, 2954, 2926, 1670, 1457, 1371, 1252, 1190,1046, 892, 844.

[0044] (2) A catalytic amount of palladium acetate was added to a 70 mldimethylsulfoxide (DMSO) solution of 3.53 g of4-methyl-1-(trimethylsilyloxy)-1-cyclohexane, followed by stirring whileintroducing oxygen for 6 hours. After the addition of water at 0° C.,the reaction mixture was filtered and then extracted with ether. Thesolvent was distilled off from the organic layer under reduced pressure.The residue was dissolved in hexane-water to extract with hexane. Thehexane layer was washed with saturated saline and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, whereby4-methyl-2-cyclohexen-1-one was obtained in the form of an oil (yield:72%).

[0045] 4-Methyl-2-cyclohexen-1-one

[0046] Molecular weight: 110 (C₇H₁₀O)

[0047] TLC: (hexane:ethyl acetate=8:2) Rf=0.35

[0048]¹H-NMR (200 MHz, CDCl₃) δ: 1.15 (d,J=7.1 Hz,3H,H-7),1.56-1.76(m,1H,H-5a), 2.1(dqa,J_(gem)=13.3 Hz,³J=4.9 Hz,1H,H-5e),2.26-2.48(m,2H,H-6), 2.49-2.62(m,1H,H-4), 5.94(dd, ³J=10.1 Hz,⁴J=2.5Hz,1H,H-2), 6.79(ddd,³J=10.1 Hz,³J=2.7 Hz,⁴J=1.5 Hz,1H,H-3).

[0049]¹³C-NMR (50 MHz, CDCl₃) δ: 20.1(C-7), 29.6(C-5), 30.9(C-4),36.8(C-6), 128.4(C-2), 156.2(C-3), 199.7(C-1).

[0050] IR(NaCl): 3025, 2958, 2932, 1683, 1617, 1458, 1391, 1375, 1251,1094, 1053, 1016, 828, 750.

[0051] (3) Sodium benzenesulfinate (3.0 g) was added to a solutioncontaining 1.52 g of 4-methyl-2-cyclohexen-1-one and 9 ml of water. 1NHydrochloric acid (18 ml) was added dropwise to the resulting solution.After stirring at room temperature for 24 hours, the crystals soprecipitated were filtered and washed with water, isopropanol and coldether. After recrystallization from isopropanol,4-methyl-3-(phenylsulfonyl)-cyclohexan-1-one was obtained in the form ofwhite crystals (yield: 72%).

[0052] 4-Methyl-3-(phenylsulfonyl)-cyclohexan-1-one

[0053] Molecular weight: 252 (C₁₃H₁₆O₃S)

[0054] Melting point: 71 to 74° C.

[0055] TLC: (hexane:ethyl acetate=6:4) Rf=0.2

[0056]¹H-NMR (200MHz, CDCl₃),

[0057] -trans δ: 1.32(d,J=6.9 Hz,3H,H-7), 1.5-1.7(m,1H,H-5), 2.15-2.3(m,1H,H-5), 2.35-2.5(m,3H,H-4,6), 2.55-2.68(m,2H,H-2), 3.17(ddd,J=8Hz,J=6.6 Hz,J=6.4 Hz,1H,H-3), 7.52-7.72(m,3H,H ar.-3′,4′),7.83-7.9(m,2H,H ar.-2′),

[0058] -cis δ: 1.44(d,J=7.1 Hz,3H,H-7), 1.75-1.9(m,1H,H-5), 1.95-2.1(m,1H,H-5), 2.23-2.5(m,3H,H-4,6), 2.73-2.9(m,2H,H-2), 3.34(dt,J=12.9Hz,J=4 Hz,1H,H-3), 7.52-7.72(m,3H,H ar.3′,4′), 7.83-7.9(m,2H,H ar.-2′).

[0059]¹³C-NMR (50 MHz, CDCl₃)

[0060] -trans δ: 20.3(C-7), 28.5(C-4), 30.4(C-5), 37.9(C-6 or -2),38.6(C-2 or -6), 66.3(C-3), 128.6(C ar.-2′ or -3′), 129.1 (C ar.-3′ or-2′), 133.9 (C ar.-4′), 137.2 (C ar.-1′), 206.6(C-1).

[0061] -cis δ: 13(C-7), 27.2(C-4), 31.1(C-5), 35.9(C-6 or -2), 36.9(C-2or -6), 64.6(C-3), 128.3(C ar.-2′ or -3′), 129.1(C ar.-3′ or -2′),133.9(C ar.-4′), 138(C ar.-l′), 206.6(C-1).

[0062] MS(EI): 111.1 (M-SO₂Ph,88), 110.1(27), 83, 15(32), 77.1 (29),69.1(36), 55.2(100).

[0063] (4) To a solution of 2.45 g of4-methyl-3-(phenylsulfonyl)-cyclohexan-1-one dissolved in 40 ml ofbenzene, were added 0.7 ml of 1,2-ethanediol and 0.2 g ofparatoluenesulfonic anhydride. The resulting mixture was heated underreflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonatesolution was added and the resulting mixture was extracted with ethylacetate three times. The combined organic layers were washed withsaturated saline, and dried over magnesium sulfate. The solvent was thendistilled off under reduced pressure. The residue was recrystallizedfrom ether, whereby1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane was obtainedin the form of white crystals (yield: 97%).

[0064] 1,1-Ethylenedioxy-4-methyl-3-phenylsulfonyl-cyclohexane

[0065] Molecular weight: 296 (C₁₅H₂₀O₄S)

[0066] Melting point: 105 to 106° C.

[0067] TLC: (hexane:ethyl acetate'6:4) Rf=0.3

[0068]¹H-NMR (200 MHz, CDCl₃),

[0069] -trans δ: 1.23(d,J-6.lHz,3H,H-7), 1.37-1.77(m,6H,H2a,4,5,6),1.84(ddd,J_(gem)=12.9 Hz,³J=3.7 Hz, ⁴J=2.7 Hz,1H,H-2e), 3.02(ddd,³J=13Hz,³J=10.3 Hz,³J=3.7 Hz,1H,H-3), 3.71-3.91(m,4H,O—CH₂—CH₂—O),7.48-7.67(m,3H,H ar.-3′,4′), 7.8-7.88(m,2H,H ar.-2′)

[0070] -cis δ: 1.18(d,J=6.9 Hz,3H,H-7), 1.37-1.77(m,4H,H-5,6),1.84(ddd,J_(gem)13 Hz,³J=3.7 Hz,⁴J=2.7 Hz,1H,H-2e), 2.02(t,J=13Hz,1H,H-2a), 2.30-2.45(m,1H,H-4), 3.29(dt, ³J=13 Hz, J=3.7 Hz,1H,H-3),3.71-3.91(m,4H,O—CH₂—CH₂—O), 7.48-7.67(m,3H,H ar.-3′,4′),7.8-7.88(m,2H,H ar.-2′).

[0071]¹³C-NMR (50 MHz,CDCl₃)

[0072] -trans δ: 20.4(C-7), 31.9(C-4), 32.6(C-5), 34.1(C-6), 35.8(C-2),64.4(CH₂-0), 66.8(C-3), 107.9(C-1), 128.6(C ar.-3′ or -2′), 129 (Car.-2′ or -3′), 133.5(C ar.-4′), 138(C ar.-1′).

[0073] -cis δ: 12.4(C-7), 26.7(C-4), 29.2(C-5,6), 32(C-2), 64.1(C-3),64.4(CH₂—O),108.2(C-1), 128.3(C ar.-2′,3′), 133.5(C ar.-4′), 138.5(Car.-1′)

[0074] IR(KBr): 3060, 2968, 2938, 1583, 1448, 1301, 1267, 1158, 1144,1082, 1023, 939, 916, 838, 749, 718, 689.

[0075] Elementary analysis (%):

[0076] Calculated: C; 60.79, H; 6.8

[0077] Found: C; 60.5, H: 6.9

[0078] (5) A solution of n-butyl lithium (1.8 ml) was added dropwise toa 5 ml THF solution of 560 mg of1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane and 4 mg oftriphenylmethane under an argon gas stream at −78° C. The resultingmixture was stirred for 10 minutes and then reacted at room temperaturefor one hour. HMPT (1 ml) was added and the resulting mixture was cooledto −78° C. again, followed by the dropwise addition of a 2 ml THFsolution of 205 mg of 14-bromo-1-tetradecanol. After reaction at −20° C.for 2 hours, the reaction mixture was poured into a saturated solutionof ammonium chloride. The resulting mixture was extracted with ether.The organic layer was washed with water and saturated saline, dried overmagnesium sulfate and distilled under reduced pressure to remove thesolvent. The residue was purified by chromatography on a silica gelcolumn while using hexane-ethyl acetate, whereby1,1-(ethylenedioxy)-3-(14-hydroxytetradecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexanewas obtained in the form of a colorless oil (yield: 98%).

[0079]1-1-(Ethylenedioxy)-3-(14-hydroxytetradecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexaneMolecular weight: 508 (C₂₉H₄₈O₅S)

[0080] TLC: (hexane:ethyl acetate=60:40) Rf=0.22

[0081]¹H-NMR (200 MHz) δ: 1.13(d,J=6 Hz,3H,H-21), 1.28(s large, 20H,H-9a H-18), 1.43-1.6(m,9H,H-4,5,7,8,19), 1.67(m,1H,H-2),1.89(dd,J_(gem)=12.5 Hz,J=3 Hz,1H,H-6e), 2.14(t large, J=12.5Hz,1H,H-6a), 2.43(dd,J_(gem)=13.8 Hz,⁴J=2.5 Hz,1H,H-2), 3.63(t,J=6.5Hz,2H,H-20), 3.83-3.97(m,4H,O—CH₂—CH₂—O), 7.49-7.68(m,3H,H ar.-3′,4′),7.80-7.88(m,2H,H ar.-2′).

[0082]¹³C-NMR (50 MHz) δ: 16.1(C-21), 24.4(C-18), 25.6(C-5 or -7),25.8(C-7 or -5), 29.5(C-9 to C-17), 30.3(C-8), 32.7(C-19), 34.9(C-6),35.5(C-4), 36.2(C-2), 62.8(C-20), 63.9 and 65.1(O—CH₂—CH₂—O), 7.12(C-3),108.4(C-1), 128.7(C ar.-3′), 130.1 (C ar.-2′), 133.3(C ar.-4′), 136.8(Car.-1′)

[0083] IR(NaCl): 3510(m large, O—H), 3063(f,C—H), 2926, 2853 (f, C—H),1585(f,C—C), 1447 (m), 1286, 1140(F,SO₂), 1096, 1083 (m,O—CH₂), 723,693(m)

[0084] MS(Cl—NH₃): 526.4 (MNH₄, 16), 369.4 (MH₂—SO₂Ph,28),370.4(MH—SO₂Ph,25), 367.3(M—SO₂Ph,100), 311.3(7), 307.3(8), 305.3(9),175(17), 159.9(11), 98.9(35), 94(6), 78(11).

[0085] Elementary analysis (%):

[0086] Calculated: C; 67.98, H; 9.37

[0087] Found: C; 67.4, H; 9.1

[0088] (6) Paratoluenesulfonic acid (20 mg) was added to a solution of235 mg of1,1-(ethylenedioxy)-3-(14-hydroxytetradecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexanein 20 ml of chloroform and 4 ml of acetone. The resulting mixture wasreacted at 50° C. for 24 hours. To the reaction mixture was added 10 mlof a saturated aqueous solution of sodium bicarbonate, followed byextraction with dichloromethane. The organic layer was washed withsaturated saline, dried over magnesium sulfate and distilled underreduced pressure to remove the solvent. The residue was purified bychromatography on a silica gel column while using hexane-ethyl acetate,whereby 3-(14-hydroxytetradecyl)-4-methyl-2-cyclohexen-1-one wasobtained in the form of a colorless oil (yield: 75%).

[0089] 3-(14-Hydroxytetradecyl)-4-methyl-2-cyclohexen-1-one

[0090] Molecular weight: 322 (C₂₁H₃₈O₂)

[0091] TLC: (hexane:ethyl acetate=6:4) Rf=0.3

[0092] MS (EI): 322.2 (M+,37), 304.1(M—H₂O,12), 292.1(21),164.9(C₁₁H_(l7)O,9), 151(C₁₀H₁₅O,4), 138.1(12), 137(C₉H₁₃O,43), 96(30),94.9(24), 81(24), 78.9(13), 69(15), 67(25), 55(37).

[0093] Elementary analysis (%)

[0094] Calculated: C; 78.20, H; 11.88

[0095] Found: C; 78.6, H; 11.9

Preparation Example 2

[0096] In a similar manner to Preparation Example 1,3-(15-hydroxypentadecyl)-4-methyl-2-cyclohexen-1-one (Compound 2) wassynthesized.

Preparation Example 3

[0097] To a methanol solution (8 ml) containing 132 mg (0.36 mmol, 1equivalent) of3-(12-acetoxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one were added 3drops of water and 74 mg (0.54 mmol, 1.5 equivalents) of K₂CO₃. Theresulting mixture was stirred at room temperature for 2.5 hours. Afteradjustment to pH 7 with 5% HCl, the reaction mixture was extracted withether, dried over magnesium sulfate and distilled under reduced pressureto remove the solvent. The residue was purified by chromatography on asilica gel column, followed by elution with hexane-ethyl acetate (8:2 to7:3), whereby 94 mg (yield: 81%) of3-(12hydroxydodecyl)-2,4,4-trimethyl-2-cyclohexen-1-one (Compound 3) wasobtained in the form of a colorless oil.

[0098] 3-(12-Hydroxydodecyl)-2,4,4-trimethyl-2-cyclohexen-1-one

[0099] TLC: (hexane:ethyl acetate=7:3) Rf=0.2

[0100] GC: 40 to 280° C. (20° C./min) 12 min, 99%

[0101]¹H-NMR (200 MHz) δ: 1.13 (ds,6H,H-19,20), 1.26(s,br,16H,H-9 toH-16), 1.35-1.69(m,4H,H-8,17), 1.73(s,3H,H-21), 1.77(t,J=7.5 Hz,2H,H-5),2.11-2.19(m,2H,H-7), 2.43(t,J=6.8 Hz,2H,H-6), 3.61(t,J=6.8 Hz,2H,H-18).

[0102]¹³C-NMR (50 MHz) δ: 11.4(C-21), 25.7(C-16), 26.8(C-19,20),28.8(C-8), 29.5(C-9 to C-15), 30.45(C-7), 32.7(C-17), 34.2(C-5),36.2(C-4), 37.3(C-6), 62.9(C-18), 130.4(C-2), 165.4(C-3), 199(C-1).

[0103] IRν: 3440 (broad OH), 2925, 2852(w,C—H), 1666(w,C═O),1605(s,C═C), 1467(s,C—H).

Preparation Example 4

[0104] In a similar manner to Preparation Example 3, the below-describedcompound was obtained. The numeral in parentheses indicates the Rf valueof TLC with a 7:3 mixed eluent of hexane and ethyl acetate.

[0105] (1) 3-(15-Hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen1-one(Compound 4) (Rf=0.29)

[0106] (2) 3-(18-Hydroxyoctadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one(Compound 5) (Rf=0.25)

[0107] Test 1 (Neural Stimulus Conduction Rate)

[0108] To a rat, 65 mg/kg of streptozotocin (STZ) was administeredintraperitoneally to prepare a model rat of diabetes. Afterintraperitoneal administration of Compound 4 obtained in PreparationExample 4 at a daily dose of 8 mg/kg for 8 weeks from two days afteradministration of STZ, the conduction rate of stimulus to sciatic nervewas measured by inserting a needle electrode for potential measurementinto the vicinity of the right sciatic nerve, right Achilles tendon, andright plantar. Measurement was conducted three times and the mean ofthem was designated as the nerve stimulus conduction rate of the rat.Each group consisted of 10 to 12 rats.

[0109] As a result, as shown in Table 1, the conduction rate was 49.4m/sec on average in a diabetes-free rat group, while it was 42.4 m/secon average in an administration-free group of diabetes rats, showinglowering in a nerve stimulus conduction rate in the latter group. In theCompound-4-administered group, on the other hand, the rate was 45.5m/sec on average, showing that administration significantly suppressedthe lowering in a nerve stimulus conduction rate resulting fromdiabetes. TABLE 1 (mean ± S.E.) Compound- Diabetes-free rat Diabetesadministered group (control) rat group group Conduction rate of 49.4 ±1.8 42.4 ± 0.5* 45.5 ± 1.2** stimulus to nerve (m/sec)

[0110] Test 2 (Maximum Quantity Excreted by Single Urination)

[0111] In a similar manner to Test 1, Compound 4 obtained in PreparationExample 4 was administered intraperitoneally to a rat at a daily dose of8 mg/kg day for 8 weeks from two days after administration of STZ. Itsurination pattern such as urination frequency and urination amount wasthen recorded for 24 hours at 2.5-min intervals by using a metaboliccage.

[0112] As a result, as shown in Table 2, the maximum quantity excretedby single urination was 4.89±0.38 ml in the administration-free diabetesrat group, while that of the Compound-4-administered rat group was3.71±0.26 ml, showing a significant decrease in the quantity. Thus, ithas been found that administration brought about an improvement. TABLE 2(mean ± S.E.) Diabetes-free rat Diabetes Administered group (control)rat group group Maximum amount 1.47 ± 0.10 4.89 ± 0.38* 3.71 ± 0.26**excreted by single urination (ml)

[0113] Test 3 (Bladder Capacity and Urination Efficiency)

[0114] In a similar manner to Test 1, Compound 4 obtained in PreparationExample 4 was administered intraperitoneally to a rat at a daily dose of8 mg/kg for 8 weeks from two days after administration of STZ. Theintravesical pressure of the rat was then measured under anesthesia,whereby bladder capacity and urination efficiency were determined.

[0115] As a result, as shown in Table 3, the urination-inducing bladdercapacity of a diabetes-free rat group was 0.25±0.03 ml, while that of anadministration-free diabetes rat group was 0.90±0.14 ml, showing adeterioration in the bladder function. That of a Compound4-administereddiabetes rat group was, on the other hand, 0.54±0.07 ml, showing asignificant improvement compared with the administration-free group.

[0116] The urination efficiency was determined from an excretedquantity/bladder capacity ratio. The diabetes-free rat group exhibited aurination efficiency of 87.5±2.2%, while the-administration-freediabetes rat group exhibited 53.6±6.5%, showing a reduction in theefficiency. The Compound-4-administered diabetes rat group, on the otherhand, exhibited 75.0±6.1%, showing a significant improvement comparedwith the administration-free group. TABLE 3 (mean ± S.E.) Test-compound-Diabetes-free rat Diabetes administered group (control) rat group groupBladder capacity 0.25 ± 0.03 0.90 ± 0.14* 0.54 ± 0.07** (ml) Urinationefficiency 87.5 ± 2.2  53.6 ± 6.5*  75.0 ± 6.1**  (%)

[0117] Urination efficiency (%)=100×excreted quantity/bladder capacity

INDUSTRIAL APPLICABILITY

[0118] The cyclohexenone long-chain alcoholic derivatives according tothe present invention significantly suppress a reduction in a peripheralnerve conduction rate in the animal models of diabetes and alleviate ahypofunction of the bladder so that it is useful as a remedy fordiabetes complications, particularly, for diabetes neuropathy.

1. A preventive and/or therapeutic agent for diabetic complications,which comprises as an effective ingredient a cyclohexenone long-chainalcoholic derivative represented by the following formula (1):

wherein, R¹, R² and R³ each independently represents a hydrogen atom ora methyl group and x represents a linear or branched C₁₀₋₂₈ alkylene oralkenylene group.
 2. A preventive and/or therapeutic agent according toclaim 1, which serves as a diabetic neuropathy alleviative.
 3. Apharmaceutical composition for preventing and/or treating diabeticcomplications, which comprises a cyclohexenone long-chain alcoholicderivative according to claim 1 and a pharmaceutically acceptablecarrier.
 4. Use of a cyclohexenone long-chain alcoholic derivativeaccording to claim 1 for the manufacture of a preventive and/ortherapeutic agent for diabetic complications.
 5. A method for preventingand/or treating diabetic complications, which comprises administering acyclohexenone long-chain alcoholic derivative according to claim 1.